The ER/SR Ca2+ sensing protein STIM1 is essential for normal cardiomyocyte function (1150.8)

Abstract

Store‐operated Ca2+ entry (SOCE) and its molecular mediator, the endoplasmic reticulum (ER) Ca2+ sensor, Stromal interaction molecule 1 (STIM1) have been implicated in hypertrophic signaling. However, since the physiological role of STIM1 in the adult heart remains unknown, we developed a cardiomyocyte‐restricted STIM1 knockout (crSTIM1‐KO) mouse. Using serial echocardiography and histological analysis, we observed a progressive decline in contractile function from 20 weeks of age, which was associated with marked left ventricular dilatation by 36 weeks. Immunoblot analyses revealed that crSTIM1‐KO hearts exhibit increased ER stress prior to contractile dysfunction (i.e., 12 weeks old) as indicated by increased levels of CHOP. Electron microscopy revealed ER dilatation, mitochondrial disorganization and smaller mitochondria in crSTIM1‐KO hearts, which was associated with a decrease in mitofusin 2 and an increase in Drp1 consistent with increased mitochondrial fission. Interestingly, perfused hearts from 20 week crSTIM1‐KO mice exhibited significant reductions in both glucose oxidation and net lactate release. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiomyocyte function in the adult heart and may be mediated through regulation of ER/ mitochondrial function and/or metabolism.Grant Funding Source: Supported by NIH grants HL101192 and HL110366 and William W Featheringill Postdoctoral Fellowship